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  • 1.
    Eriksson, David
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Blomberg, Jeanette
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lindgren, Theres
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Löfroth, Per-Olov
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Iodine-131 induces mitotic catastrophes and activates apoptotic pathways in HeLa Hep2 cells2008In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 23, no 5, p. 541-549Article in journal (Refereed)
    Abstract [en]

    Iodine-131 (131I) has been used both in unconjugated form and conjugated to antibody derivates (i.e., radioimmunotherapy; RIT) to treat malignant diseases. The mechanisms by which 131I-irradiation causes growth retardation are, however, inadequately understood. The aim of this study was to elucidate the sequential molecular and cellular events that initiate cell death in HeLa Hep2 cells exposed to 131I. In this paper, HeLa Hep2 cells were found to display a transient G2-M arrest following irradiation, but then reentered the cell cycle still containing unrepaired cellular damage. An increase of multipolar mitotic spindles, as well as a significant increase in centrosome numbers from 8.8% +/- 1.9% in controls to 54.7% +/- 2.2% in irradiated cells, was observed (p < 0.0001). A subsequent failure of cytokinesis caused the cells to progress into mitotic catastrophe. This was accompanied by the formation of giant cells with multiple nuclei, multilobulated nuclei, and an increased frequency of polyploidy cells. A fraction of the cells also displayed apoptotic features, including the activation of initiator caspases-2, -8, -9, and effector caspase-3, as well as cleavage of poly(ADP-ribose) polymerase, a cell-death substrate for active caspase-3. These findings demonstrate that mitotic catastrophes and the activation of a delayed type of apoptosis might be important mechanisms involved in cell death following the RIT of solid tumors with -emitting radionuclides, such as 131I.

  • 2.
    Gustafsson, Sofia B
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Lindgren, Theres
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Jonsson, Maria
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Jacobsson, Stig OP
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Cannabinoid receptor-independent cytotoxic effects of cannabinoids in human colorectal carcinoma cells: synergism with 5-fluorouracil2009In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 63, no 4, p. 691-701Article in journal (Refereed)
    Abstract [en]

    Cannabinoids (CBs) have been found to exert antiproliferative effects upon a variety of cancer cells, including colorectal carcinoma cells. However, little is known about the signalling mechanisms behind the antitumoural effect in these cells, whether the effects are shared by endogenous lipids related to endocannabinoids, or whether such effects are synergistic with treatment paradigms currently used in the clinic. The aim of this preclinical study was to investigate the effect of synthetic and endogenous CBs and their related fatty acids on the viability of human colorectal carcinoma Caco-2 cells, and to determine whether CB effects are synergistic with those seen with the pyrimidine antagonist 5-fluorouracil (5-FU). The synthetic CB HU 210, the endogenous CB anandamide, the endogenous structural analogue of anandamide, N-arachidonoyl glycine (NAGly), as well as the related polyunsaturated fatty acids arachidonic acid and eicosapentaenoic acid showed antiproliferative and cytotoxic effects in the Caco-2 cells, as measured by using [3H]-thymidine incorporation assay, the CyQUANT proliferation assay and calcein-AM fluorescence. HU 210 was the most potent compound examined, followed by anandamide, whereas NAGly showed equal potency and efficacy as the polyunsaturated fatty acids. Furthermore, HU 210 and 5-FU produced synergistic effects in the Caco-2 cells, but not in the human colorectal carcinoma cell lines HCT116 or HT29. The compounds examined produced cytotoxic, rather than antiproliferative effects, by a mechanism not involving CB receptors, since the CB receptor antagonists AM251 and AM630 did not attenuate the effects, nor did pertussis toxin. However, α-tocopherol and the nitric oxide synthase inhibitor L-NAME attenuated the CB toxicity, suggesting involvement of oxidative stress. It is concluded that the CB system may provide new targets for the development of drugs to treat colorectal cancer.

  • 3.
    Lindgren, Theres
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Optimizing experimental radioimmunotherapy: investigating the different mechanisms behind radiation induced cell deaths2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background. Radiation therapy is an important treatment regimen for malignant disease. Radiation therapy uses ionizing radiation to induce DNA damage in tumor cells in order to kill them. Tumor cells are more sensitive than normal cells, since they have an increased proliferation rate and often lack the ability to properly repair the induced damage. Radiation can be delivered by an external source outside the body, by brachytherapy delivered inside the patient near the tumor, or systemically by injection into the blood stream. When delivered systemically, the radiation is administered as radioisotope alone or conjugated to antibodies targeting tumor antigens (radioimmunotherapy). Radiotherapy (RT) usually is administered using high doses, causing necrotic cell death. Low doses of radiation (by RT or RIT) have been observed to induce different types of cell deaths, like apoptosis, mitotic catastrophe or senescence.Aims. We wanted to elucidate the molecular and cellular events responsible for the induction of cell death in cells of different origin and p53 status. We also wanted to identify the kinetics behind gene expression alterations induced in response to irradiation and correlate these to cell death specific molecular and cellular events. In the end this research aims to identify key regulators of the main radiation induced cell death modalities in order to improve our understanding and potentially use this knowledge to increase treatment efficacy of radiation therapy.

    Methods. Four different cell lines were used in these studies to elucidate the role of p53 status cell origin in radiation induced cell death. HeLa Hep2 tumor cells have been used previously in our group in several RIT and RT studies. During these studies we observed morphological alterations in shrinking tumors that were typical for mitotic catastrophe. This led to studies on the underlying mechanisms causing these aberrations. Isogenic solid tumor cell lines HCT116 p53 +/+ and HCT116 p53 -/- were included to further elucidate the role of p53, and also to study senescence, one of the main outcomes in irradiated tumor cells. MOLT-4 was finally included to compare these finding to classical apoptosis. Gene expression analysis was done using Illumina bead chip arrays, and pathway analysis was performed using MetaCore (Thomson Reuters).

    Results. In paper I, II, and III, transient G2/M arrests were observed in HeLa Hep2 and HCT116 p53 -/- cells following irradiation. The lack of p53 in these cells caused checkpoint adaptation due to an unscheduled accumulation of genes promoting mitosis. Anaphase bridges were observedivin HeLa Hep2 cells, as a consequence of premature mitotic entry with unrepaired DNA damage. Centrosome amplification, as well as deregulation of genes involved in centrosome amplification and clustering was observed in both cell lines. We observed changes in expression of several genes responsible for maintaining the spindle assembly checkpoint (SAC) arrest. A prolonged SAC arrest has been shown to be important for execution of mitotic catastrophe. SAC activation was followed by mitotic slippage and a subsequent failure of cytokinesis. We observed multipolar mitoses (both cell lines), multiple- and micronuclei (HeLa Hep2, paper I), and an increased frequency of tetraploid cells (HeLa Hep2 and HCT116 p53 -/- cells). A fraction of HeLa Hep2 cells also displayed apoptotic features, including caspase activation and DNA fragmentation (paper I). These findings indicate that mitotic catastrophe and the activation of a delayed type of apoptosis are involved in cell death following RIT.HCT116 p53 +/+ cells induced both G1 and G2 arrest following irradiation (paper III). Gene expression analysis revealed significantly decreased expression of genes responsible for cell cycle progression (pronounced decrease compared to HeLa Hep2 and HCT116 p53 -/-), especially mitotic genes. The prolonged arrest transitioned into senescence starting 3 days following irradiation and peaked after 7 days. Several genes associated with SASP were upregulated in the same time frame as senescence was induced, further supporting the fact that senescence is the main radiation induced response in HCT116 p53 +/+ cells.MOLT-4 cells, similar to HCT116 p53 +/+ cells, induced both G1 and G2 arrests in response to irradiation (paper IV). Morphological studies revealed apoptotic features like shrunken cells with condensed DNA. Caspase assays showed increased activity of caspases -3, -8, and -9. Gene expression analysis confirmed an increased expression of genes important for both extrinsic (FAS and TRAIL) and intrinsic (BAX) apoptosis. Furthermore, changed expression also included genes involved in cell cycle checkpoints and their regulation and genes important for T-cell activation/proliferation.

    Conclusions. RIT is successfully used to treat lymphoma, but treatment of solid tumors with RIT is still difficult. This thesis elucidates cellular alterations characteristic for the 3 main radiation death modalities, i.e. mitotic catastrophe, senescence and apoptosis. Furthermore, cell death specific traits are correlated to alterations in gene expression. Treatment efficacy can potentially be improved by finding key cell death mediators to inhibit in combination with radiation.

  • 4.
    Lindgren, Theres
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Erikssom, David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Alterations in gene expression during radiation induced mitotic catastrophe in HeLa Hep2 cellsManuscript (preprint) (Other academic)
    Abstract [en]

    Purpose: To explore kinetic changes in the gene expression profile during radiation induced mitotic catastrophes.

    Methods and Materials: We measured temporal global gene expression in HeLa Hep2 tumor cells using bead chip arrays (Illumina) following exposure to 5 Gy of ionizing radiation (60Co). Genes with less than a 2-fold change in expression and a p-value > 0.05 were discarded. Signaling pathways significantly altered following irradiation were explored using Metacore. Furthermore, biological responses linked to mitotic catastrophe including cell cycle arrests, anaphase bridge formation and centrosome amplification were analyzed and correlation to gene expression changes evaluated.

    Results: Following irradiation a G2-arrest was induced. This arrest was transient and cells entered mitosis before DNA damage was repaired causing anaphase bridge formation. Furthermore, radiation induced hyperamplification of centrosomes was observed. These phenotypical changes correlated well with the observed gene expression changes. At 6 h following irradiation the expression was changed only for a few genes including histone H2 and H4, essential for activation of a DNA-damage checkpoint. Striking changes appeared at later time-points. From 12-96 hours post irradiation a significant fraction of the genes with altered expression were found to be involved in cell cycle progression and its regulation. The significant changes were seen for genes important for several mitotic processes, and those involved in the G2- and spindle assembly checkpoints. Also centrosome associated genes displayed an increased expression. Furthermore, 96 hours after irradiation pathways involved in immune and inflammatory responses were significantly altered.

    Conclusions: This study elucidates specific characteristics in the altered gene expression pattern induced by irradiation, which can be linked to the sequential steps observed in HeLa Hep2 cells during mitotic catastrophes. Therapeutic strategies employing these alterations might potentiate future therapy and enhance tumor cell killing.

  • 5.
    Lindgren, Theres
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Eriksson, David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Alterations in Gene Expression During Radiation-Induced Mitotic Catastrophe in He La Hep2 Cells2014In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 34, no 8, p. 3875-3880Article in journal (Refereed)
    Abstract [en]

    Aim: To explore kinetic changes in the gene expression profile during radiation-induced mitotic catastrophes. Materials and Methods: Gene expression changes were measured in HPV-infected HeLa Hep2 tumor cells following exposure to 5 Gy of ionizing radiation (Co-60). Signaling pathways were explored and correlated to the biological responses linked to mitotic catastrophe. Results: Following irradiation a transient G(2)-arrest was induced. Anaphase bridge formation and centrosome hyperamplification was observed. These phenotypical changes correlated well with the observed gene expression changes. Genes with altered expression were found to be involved in mitotic processes as well as G(2)- and spindle assembly checkpoints. Also centrosome-associated genes displayed an increased expression. Conclusion: This study elucidates specific characteristics in the altered gene expression pattern induced by irradiation, which can be correlated to the events of mitotic catastrophe in HeLa Hep2 cells. Therapeutic strategies modulating these alterations might potentiate future therapy and enhance tumor cell killing.

  • 6.
    Lindgren, Theres
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Raberg, A
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Eriksson, David
    Genome wide expression analysis of radiation induced DNA damage responses in isogenic HCT 116 cell lines2012In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, no Suppl. 1, p. 76-76Article in journal (Other academic)
  • 7.
    Lindgren, Theres
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Eriksson, David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Gene expression profiling in MOLT-4 cells during gamma-radiation-induced apoptosis2012In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, no 3, p. 689-700Article in journal (Refereed)
    Abstract [en]

    This study aims to identify the temporal changes in gene expression in MOLT-4, a leukemia cell line, in response to radiation and to present a comprehensive description of the pathways and processes that most significantly relate to the cellular biological responses. A global gene expression profile of 24,500 genes was performed on MOLT-4 tumor cells following exposure to 5 Gy of ionizing radiation (Co-60) using a bead chip array (Illumina). Signaling pathways and processes significantly altered following irradiation were explored using MetaCore. Cellular viability [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide], activation of cell cycle checkpoints [fluorescence activated cell sorting (FACS)], and induction of apoptosis (FACS, caspase assays) were evaluated to correlate these biological responses to the gene expression changes. Totally, 698 different genes displayed a significantly altered expression following radiation, and out of these transcripts, all but one showed increased expression. One hour following irradiation, the expression was changed only for a few genes. Striking changes appeared at later time-points. From 3 to 24 h post-irradiation, a significant fraction of the genes with altered expression were found to be involved in cell cycle checkpoints and their regulation (CDKN1A), DNA repair (GADD45A, DDB2, XPC), apoptosis induction (DR5, FasR, Apo-2L, Bax), and T-cell activation/proliferation (CD70, OX40L). Irradiated MOLT-4 cells were arrested at the G2-checkpoint, followed by a decrease in cell viability, most pronounced 48 h after exposure. The cell death was executed by induced apoptosis and was visualized by an increase in subG1 cells and an increased activation of initiator (caspase-8 and caspase-9) and execution (caspase-3) caspases. Activation of cell cycle arrest and apoptosis correlated well in time with the changes in gene expression of those genes important for these biological processes. Activation of the apoptotic signaling pathways in MOLT-4 cells following irradiation includes components from the intrinsic as well as the extrinsic apoptotic pathways. This study indicates that the altered gene expression pattern induced by irradiation is important for the sequential steps observed in MOLT-4 cells during apoptosis induction.

  • 8.
    Lindgren, Theres
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Råberg, Aino
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Eriksson, David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Genome wide expression analysis of radiation induced DNA damage responses in isogenic HCT116 p53 +/+ and HCT116 p53 -/- colorectal carcinoma cell lines2015In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 91, no 1, p. 99-111Article in journal (Refereed)
    Abstract [en]

    Purpose : To study the kinetics of gene expression alterations following radiation exposure of isogenic HCT116 p53+/+ and HCT116 p53-/- cell lines. Materials and methods : Cells were exposed to 5 Gy of irradiation (Cs-137) and genome-wide temporal expression analysis using Illumina bead chip arrays was performed. Signalling pathways were explored using Metacore (Genego). Biological responses including cell cycle checkpoint activation, centrosome amplification and senescence induction were analyzed. Results : Significant differences in the radiation response were observed between the p53+/+ and the p53-/- cell lines. In p53+/+ cells concurrent G1- and G2-arrests were activated followed by senescence induction. Increased expression of genes associated with senescence, senescence associated secretory phenotype (SASP) and repression of genes essential for G2-M transition were detected. P53-/- cells arrested mainly in G2 followed by centrosome amplification, mitotic slippage and a subsequent increase of polyploid cells. Furthermore, changes in expression correlated well with these signs of mitotic catastrophe. Conclusions : The presence or absence of p53 triggers different signalling cascades with different endpoints. Elucidating these differences is important as it enables improvement of radiation treatment and could be used to develop new combination treatments with specific inhibitors of key regulators of these cell death modalities.

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